The proline-rich SH3-binding (SH3B) motif of the tyrosine kinase-interacting protein (Tip) of herpesvirus saimiri (HVS) is required for binding to the cellular Src family kinase Lck We constructed a mutant form of HVS in which prolines in the SH3B motif of Tip were altered to alanines This mutant form of Tip was incapable of binding to Lck The mutant virus, HVS/Tip mSH3B, retained its ability to immortalize common marmoset lymphocytes in culture In fact, common marmoset lymphocytes immortalized by the HVS/Tip mSH3B mutant displayed increased expression of HLA-DR lymphocyte activation marker, an altered pattern of tyrosine phosphorylation, increased expression of the tyrosine kinase Lyn, and a shift in electrophoretic mobility of Lck compared to cells immortalized by wild-type HVS Experimental infection of common marmosets resulted in fulminant lymphoma with both HVS/Tip mSH3B and wild-type HVS However, HVS/Tip mSH3B produced greater infiltration of affected or gans by proliferating lymphoid cells compared to wild-type HVS These results demonstrate that Tip binding to Lck is not necessary for transformation and that abrogation of Tip binding to Lck alters the characteristics of transformed cells and the severity of the pathologic lesions PUBLICATIONS Lee, H, Veazey, R, Williams, K, Li, M, Guo, J, Neipel, F, Fleckenstein, B, Lackner, A, Desrosiers, RC, and Jung, JU Mutation of the Lck-binding motif of tip enhances lymphoid cell activation by herpesvirus saimiri J Virol 1998; 72:2607-2614